Hypertension is a major public health concern in the U.S. with ~70 million adults affected including Veterans. It is the primary risk-factor for development of stroke and heart failure and the second most common cause of kidney failure. Prompt diagnosis and effective treatment are suboptimal with only 60% of Veterans meeting the 7th Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) recommendation of arterial pressure <140/90 mmHg. While essential hypertension is most common, the prevalence of atherosclerotic renovascular hypertension is rising with prevalence as high as 50% in high risk patients who have concurrent extrarenal atherosclerosis and heart failure. Renal artery stenosis occurred in 28% of Veterans undergoing cardiac catheterization with a greater than 3-fold risk in those over age 65. The benefits of angioplasty with or without stenting in controlling arterial pressure, decreasing cardiac or renal events, or reducing morbidity and mortality remain unproven and controversial. Surgical intervention and inhibition of angiotensin II carry substantial risk. Thus, it is important to seek alternative or adjunctive strategies. Regular exercise is a mainstay of rehabilitative strategies and is key to cardiovascular health. Sedentary lifestyle is widespread and many veterans suffer from injuries or diseases that limit dynamic exercise: amputation, paralysis, peripheral vascular disease, cardiopulmonary disorders, and even depression. In addition to decreasing arterial pressure, regular dynamic exercise decreases sympathetic outflow which independently contributes to greater cardiovascular risk. While these mechanisms have been explored in essential hypertension, they have received little attention in renovascular disease. Thus, we will test the hypothesis that in a model of renovascular hypertension, the two-kidney one-clip (2K1C) rat, dynamic exercise training decreases systemic blood pressure by decreasing afferent neural inputs from the stenosed kidney thereby enhancing central nitritergic signaling and decreasing renal sympathetic nerve activity that regulates distal tubular sodium reabsorption. Three Specific Aims will be addressed: (1) We will assess whether exercise training will decrease arterial pressure and contralateral RSNA in 2K-1C (or sham-clipped) rats via inhibition of afferent nerve inputs from the clipped kidney; (2) We will evaluate whether exercise training influences RSNA by enhancing nitritergic signaling within the paraventricular nucleus whose neurons project to brainstem cardiovascular centers as well as directly to the kidney; and (3) We will determine the effect of exercise trainin on renin release, plasma and renal tissue Ang II and renal sodium excretion via the distal sodium chloride co-transporter (NCC) and epithelial sodium channel (ENaC). We perform our hemodynamic, renal nerve recordings and measurements of plasma angiotensin II and aldosterone in chronically instrumented, conscious, freely moving rats, thereby minimizing the confounding affects of anesthesia. We use cryoablation of the renal nerve from the kidney with the stenosis rather than surgical denervation. This novel cryotreatment will permit us to evaluate two things: proof of concept that renal denervation will be effective and that this device may be a viable prototype for developing noninvasive methods to perform renal denervation in individuals with atherosclerotic renovascular disease. We also will apply standard clearance methodology to evaluate urinary sodium excretion as well as molecular approaches to evaluate the impact of exercise on NCC and ENaC. This research will result in findings that would directly impact the health of Veterans and achieve our long term goal of providing evidence based programs of exercise and rehabilitation, proof of principle for new cryotechniques for renal denervation that can be used in atherosclerotic renal artery stenosis, and identifying therapies that mimic the physiologic benefits exercise on sympathoexcitation and renal sodium reabsorption in Veterans who are unable to exercise due to loss of limbs, paralysis or peripheral vascular disease. PUBLIC HEALTH RELEVANCE: Narrative: Public Health Relevance Statement Hypertension is a major public health concern in the U.S. that affects ~70 million adults including an increasing number of Veterans. Physical inactivity has become a significant contributor to poor cardiovascular health and greater morbidity and mortality. Regular exercise improves blood pressure and decreases cardiovascular risk in essential hypertension. A type of hypertension due to build up of fatty plaques in the wall of the artery to the kidney, known as renovascular hypertension, is becoming more widespread. Individuals with this type of hypertension often have other medical problems that prevent them from engaging in meaningful exercise. Our proposal is designed to study the mechanisms whereby regular exercise alters the interactions between the brain and the kidneys in renovascular hypertension. By better understanding of these mechanisms we may be able to devise evidence based strategies for exercise rehabilitation programs for individuals who suffer from atherosclerotic renovascular and peripheral vascular disease and identify therapeutic targets for mimicking the benefits of exercise in individual who cannot engage in dynamic exercise, such as those who suffer from paralysis, amputation, heart failure and even depression.